WO2021143181A1

WO2021143181A1 - Method for preparing oxazole compound

Info

Publication number: WO2021143181A1
Application number: PCT/CN2020/115924
Authority: WO
Inventors: 周有桂; 陈卫勇; 赵雷; 黄尖; 王剑; 杨运晗; 陈志荣; 李浩然
Original assignee: 上虞新和成生物化工有限公司; 浙江新和成股份有限公司; 山东新和成精化科技有限公司
Priority date: 2020-01-19
Filing date: 2020-09-17
Publication date: 2021-07-22
Also published as: CN111153869A; CN111153869B

Abstract

The present invention relates to a method for preparing an oxazole compound. An additive represented by a formula (I) or (II) or (III) is added into an organic solvent and organic alkali (especially triethylamine), an organic solution of phosgene or diphosgene or triphosgene is dropwise added to perform a cyclization reaction with a compound (IV), and thus a product (V) at a high yield can be obtained and the generation of byproducts can be greatly inhibited. The reaction conditions in the present invention are mild, and compared with a method without addition of additives, the technical solution in the present invention can improve the yield of the product (V) to 95% or more and reduce the byproducts by 10% or more.

Description

A method for preparing oxazole compounds

Technical field

The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing oxazole compounds.

Background technique

Oxazole compounds are an important class of heterocyclic compounds. Some compounds with oxazole rings have biological activity and are important pharmaceutical intermediates. For example, 4-methyl-5-alkoxy-substituted oxazole compounds can be used to synthesize vitamin B6.

US3560516 discloses a method for preparing oxazole derivatives using phosgene. The method includes phosgene and N-oxalylation in the presence of an organic base such as triethylamine, in the presence or absence of an organic solvent The amino acid ester compound undergoes a cyclization reaction. This method can generally obtain oxazole derivatives with a yield of 50-80%. The main reason for the lower yield is that in the reaction system, phosgene easily reacts with triethylamine to generate a large amount of N,N-diethylformyl chloride, which consumes a large amount of phosgene (Heterocycles, 1997). , 46, 101-104; Org. Lett., 2012, 14, 3676–3679.).

CN102060801A1 discloses a method for synthesizing 5-alkoxy-substituted oxazole compounds. The method includes amino acid ester derivatives, triethylamine as an acid binding agent, and N,N-diethyl as a catalyst. In the organic solvent solution of the compound having halogen or nitro substituent at the para position of the N,N-diethylformamide group on the benzene ring of benzamide, the organic solvent solution of triphosgene is added dropwise to carry out the reaction. The yield of the target product obtained by this method is only about 80%.

CN104447605A1 discloses an industrial preparation method of 4-methyl-5-ethoxyoxazole, which comprises adding a chloroform solution containing N-ethoxyoxalanine ethyl ester, triphosgene and a catalyst pyridine or acid chloride During the reaction, triethylamine was added dropwise. The maximum yield of the target product obtained by this method is only 80%, and the method uses volatile and potentially carcinogenic chloroform as the solvent of the reaction system without mentioning whether it is suitable to use other organic solvents.

Summary of the invention

The problem to be solved by the invention

The purpose of the present invention is to provide a method for preparing oxazole compounds, which aims to solve the problem of low yield of target products in the process of preparing oxazole compounds by reacting phosgene with substrate amino acid ester derivatives in the prior art. The problem of producing a larger amount of by-products.

Solutions used to solve the problem

In order to achieve the above object, the present invention provides a method for preparing oxazole compounds, the method comprises: Ester and one or more of the aryl boronic acid compound represented by the following formula (III), the oxalylated amino acid ester compound represented by the following formula (IV) and the organic solvent solution of an organic base are added to an organic solvent solution selected from light One or more of the organic solvent solutions of phosgene, diphosgene and triphosgene are reacted to obtain the oxazole compound represented by formula (V):

In formula (I), each R ^{1 is the} same or different, and is selected from an alkyl group containing 1 to 20 carbon atoms, a cycloalkyl group containing 3 to 20 carbon atoms, or substituted or unsubstituted 6 to 20 carbon atoms. Substituted aryl groups; preferably methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, hexyl, cyclohexyl, octyl, n-undecyl, phenyl, p-methylphenyl, Or p-methoxyphenyl; more preferably phenyl, p-methylphenyl, tert-butyl, or cyclohexyl;

In formula (II), each R ^{2 is the} same or different, and is selected from an alkyl group containing 1-20 carbon atoms, a cycloalkyl group containing 3-20 carbon atoms, or substituted or unsubstituted 6-20 carbon atoms. Substituted aryl groups, preferably methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, hexyl, cyclohexyl, octyl, n-undecyl, phenyl, p-methylphenyl, Or p-methoxyphenyl; more preferably phenyl, ethyl, or isopropyl;

In formula (III), each R ^{3 is the} same or different, and is selected from hydrogen or an alkyl group containing 1 to 10 carbon atoms;

Is a substituted or unsubstituted aryl group containing 6-20 carbon atoms, preferably phenyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl, or naphthyl;

In formulas (IV) and (V), each R ^{4 is the} same or different, and is selected from alkyl groups containing 1 to 5 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, or n-butyl ; R ⁵ is H or an alkyl group containing 1 to 5 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, or n-butyl.

According to the method for preparing oxazole compounds provided by the present invention, the ratio of the mass of the oxalylated amino acid ester compound represented by formula (IV) to the total volume of the organic solvent in the reaction system is 0.05 g/mL to 1.0 g/mL, It is preferably 0.1 g/mL to 0.5 g/mL.

According to the method for preparing oxazole compounds provided by the present invention, the amount of the auxiliary agent is 0.01 to 0.2 equivalents, preferably 0.05 to 0.1 equivalents of the oxalylated amino acid ester compound represented by the formula (IV).

According to the method for preparing oxazole compounds provided by the present invention, the amount of the organic base is 0.06-6 equivalents of the amount of phosgene, preferably 1-6 equivalents; or 0.12-12 equivalents of the amount of diphosgene, preferably 2-12 equivalents; or 0.18-18 equivalents of the amount of triphosgene, preferably 3-18 equivalents.

According to the method for preparing oxazole compounds provided by the present invention, the amount of phosgene is 1 to 3 equivalents, preferably 1 to 2 equivalents, of the oxalylated amino acid ester compound represented by formula (IV); The amount of gas used is 0.5 to 1.5 equivalents, preferably 0.5 to 1 equivalent, of the oxalylated amino acid ester compound represented by the formula (IV); the amount of triphosgene is the oxalylated amino acid ester represented by the formula (IV) 0.33 to 1 equivalent of the compound, preferably 0.33 to 0.7 equivalent.

According to the method for preparing oxazole compounds provided by the present invention, the reaction temperature is -10°C to 180°C, preferably 25°C to 100°C.

According to the method for preparing oxazole compounds provided by the present invention, the trihydrocarbyl phosphine oxide represented by the formula (I) is triphenyl phosphine oxide, tri-p-methylphenyl phosphine oxide, tri-tert-butyl phosphine oxide, and tri-tert-butyl phosphine oxide. One or more of cyclohexyl phosphine oxide;

The trihydrocarbyl phosphate represented by formula (II) is one or more of triphenyl phosphate, triethyl phosphate, and triisopropyl phosphate;

The arylboronic acid compound represented by the formula (III) is one or more of phenylboronic acid, naphthaleneboronic acid, p-methoxyphenylboronic acid, and p-tolueneboronic acid.

According to the method for preparing oxazole compounds provided by the present invention, the oxalylated amino acid ester compound represented by the formula (IV) is N-ethoxy oxalyl alanine ethyl ester and N-butoxy oxalyl alanine One or more of n-butyl ester and N-methoxyoxalanine methyl ester.

According to the method for preparing oxazole compounds provided by the present invention, the organic base is pyridine, diisopropylethylamine, dimethylamine, triethylamine, 4-N,N-dimethylaminopyridine, and 4- One or more of methylimidazole, preferably triethylamine.

According to the method for preparing oxazole compounds provided by the present invention, the organic solvent is dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, chlorobenzene, toluene , Xylene, N,N-dimethylformamide, methyl tert-butyl ether, isopropyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclohexane One or more of, n-hexane, and petroleum ether; preferably dichloromethane, chloroform, 1,1,2-trichloroethane, chlorobenzene, toluene, xylene, N,N-dimethyl One or more of formamide, cyclohexane, n-hexane, and petroleum ether.

The effect of the invention

According to the method for preparing oxazole compounds provided by the present invention, the reaction conditions are mild, the reaction time is short, and the reaction efficiency is high. The oxazole product (V) can be obtained at a high yield of more than 95%, and the by-product N, The formation of N-diethylformyl chloride.

Detailed ways

The term "trihydrocarbyl phosphine oxide" as used herein refers to a compound having the structural formula shown in the following formula (I),

Wherein, each R ^{1 is the} same or different, and is selected from an alkyl group containing 1 to 20 carbon atoms, a cycloalkyl group containing 3 to 20 carbon atoms, or a substituted or unsubstituted aryl group containing 6 to 20 carbon atoms , Such as methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, hexyl, cyclohexyl, octyl, n-undecyl, phenyl, p-methylphenyl, or p-methoxy Phenyl; preferably phenyl, p-methylphenyl, t-butyl, or cyclohexyl.

The term "trihydrocarbyl phosphate" as used herein refers to a compound having the structural formula shown in the following formula (II),

Wherein, each R ^{2 is the} same or different, and is selected from an alkyl group containing 1 to 20 carbon atoms, a cycloalkyl group containing 3 to 20 carbon atoms, or a substituted or unsubstituted aryl group containing 6 to 20 carbon atoms , Such as methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, hexyl, cyclohexyl, octyl, n-undecyl, phenyl, p-methylphenyl, or p-methoxy Phenyl; preferably phenyl, ethyl, or isopropyl.

The term "aryl boronic acid compound" as used herein refers to a compound having the structural formula shown in the following formula (III),

Wherein, each R ^{3 is the} same or different, and is selected from hydrogen or an alkyl group containing 1 to 10 carbon atoms;

It is a substituted or unsubstituted aryl group containing 6-20 carbon atoms, such as phenyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl, or naphthyl.

The term "oxalylated amino acid ester compound" as used herein refers to a compound having the structural formula shown in the following formula (IV),

Wherein, each R ^{4 is the} same or different, and is selected from alkyl groups containing 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, or n-butyl; R ⁵ is H or contains 1 Alkyl groups of ~5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, or n-butyl.

The term "oxazole compound" as used herein refers to a compound having the structural formula shown in the following formula (V),

Wherein, R ⁴ and R ⁵ R in the above formula (IV) ⁴ and R ⁵ have the same meaning.

According to the method for preparing oxazole compounds provided by the present invention, it has the following reaction formula:

The inventors of the present invention have proved based on experimental results that when phosgene, diphosgene or triphosgene is used to prepare oxazole compounds, the addition of phosphorus-containing or boron-containing compounds with a specific structure will promote the efficient progress of the main reaction and prevent the side effects. The reaction has an inhibitory effect. The inventor found through experimental research that according to the method for preparing oxazole compounds provided by the present invention, the target product oxazole compound represented by formula (V) can be obtained in a high yield, and the generation of by-products can be greatly suppressed at the same time.

According to the method for preparing oxazole compounds provided by the present invention, one selected from the group consisting of trihydrocarbyl phosphine oxide represented by formula (I), trihydrocarbyl phosphate represented by formula (II), and aryl boronic acid compound represented by formula (III) At least one is used as an adjuvant. Among them, the trihydrocarbyl phosphine oxide represented by formula (I) is preferably one or more of triphenyl phosphine oxide, tri-p-methylphenyl phosphine oxide, tri-tert-butyl phosphine oxide, and tricyclohexyl phosphine oxide; The trihydrocarbyl phosphate represented by formula (II) is preferably one or more of triphenyl phosphate, triethyl phosphate, and triisopropyl phosphate; the aryl boronic acid compound represented by formula (III) is preferably phenylboronic acid One or more of, naphthalene boronic acid, p-methoxyphenyl boronic acid, and p-toluene boronic acid.

According to the method for preparing oxazole compounds provided by the present invention, the reaction substrate used is an oxalylated amino acid ester compound represented by formula (IV), which is preferably N-ethoxyoxalanine ethyl ester, N -One or more of n-butoxy oxalyl alanine n-butyl ester and N-methoxy oxalyl alanine methyl ester.

According to the method for preparing oxazole compounds provided by the present invention, the reaction temperature of the reaction system is preferably -10°C to 180°C, more preferably 25°C to 100°C.

According to the method for preparing oxazole compounds provided by the present invention, the ratio of the mass of the oxalylated amino acid ester compound represented by the formula (IV) to the total volume of the organic solvent in the reaction system is 0.05g/mL～1.0g/ mL, preferably 0.1g/mL～0.5g/mL, when it is higher than 1.0g/mL, more organic amine hydrochloride will be precipitated in the reaction, and the mass transfer effect will be worse, which is not conducive to improving the conversion rate and selectivity; less than 0.05g /mL, if the system concentration is too low, the reaction conversion rate will be reduced.

The amount of the auxiliary agent is 0.01 to 0.2 equivalents, preferably 0.05 to 0.1 equivalents, of the oxalylated amino acid ester compound represented by the formula (IV). The amount of the auxiliary agent is less than 0.01 equivalent, and the side reaction inhibitory effect becomes poor. If the amount is greater than 0.2 equivalent, it will adversely affect the subsequent purification and reaction.

The amount of the organic base is 0.06 to 6 equivalents of the amount of phosgene, preferably 1 to 6 equivalents; or 0.12 to 12 equivalents of the amount of diphosgene, preferably 2 to 12 equivalents; or 0.18 to the amount of triphosgene 18 equivalents, preferably 3-18 equivalents. When the equivalents of organic base and phosgene, diphosgene, and triphosgene are within the above range, the reaction conversion rate and selectivity are high; the ratio of organic base to phosgene, diphosgene, and triphosgene When the amount is lower than the lower limit of the above range, the conversion of raw materials is not complete. When the equivalent of organic base and phosgene, diphosgene, and triphosgene is higher than the upper limit of the above range, the organic base will react with phosgene, diphosgene, and triphosgene. , Generate more corresponding acid chlorides, resulting in waste of raw materials.

The dosage of the phosgene is 1 to 3 equivalents, preferably 1 to 2 equivalents, of the dosage of the oxalylated amino acid ester compound represented by the formula (IV); the dosage of the diphosgene is represented by the formula (IV) 0.5 to 1.5 equivalents of the oxalylated amino acid ester compound, preferably 0.5 to 1 equivalent; the amount of triphosgene is 0.33 to 1 equivalent of the oxalylated amino acid ester compound represented by the formula (IV), preferably 0.33 to 0.7 equivalent. When the equivalent weight of phosgene, diphosgene or triphosgene to the oxalylated amino acid ester compound represented by formula (IV) is lower than the lower limit of the above range, more oxalylated amino acid ester compound remains; phosgene, diphosgene or triphosgene When the equivalent of gas and the oxalylated amino acid ester compound represented by formula (IV) is higher than the upper limit of the above range, more acid chlorides are generated, and reaction selectivity is reduced, and the auxiliary agent does not have an effective inhibitory effect.

According to the method for preparing oxazole compounds provided by the present invention, the organic solvent used is an organic solvent that can dissolve the reactants and assistants of the present invention, and is inert to the reactants and assistants of the present invention. In a preferred case, examples of the organic solvent include dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, chlorobenzene, toluene, xylene, N, N-dimethylformamide, methyl tert-butyl ether, isopropyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclohexane, n-hexane, and petroleum One or more of ethers; in particular, dichloromethane, chloroform, 1,1,2-trichloroethane, chlorobenzene, toluene, xylene, N,N-dimethylformamide are more preferred One or more of, cyclohexane, n-hexane, and petroleum ether.

According to the method for preparing oxazole compounds provided by the present invention, in a preferred case, the organic base used is pyridine, diisopropylethylamine, dimethylamine, triethylamine, 4-N,N-dimethylamine One or more of aminopyridine, and 4-methylimidazole; particularly preferred is triethylamine.

According to the method for preparing oxazole compounds provided by the present invention, the preferred embodiment is: dissolving the oxalylated amino acid ester compound represented by formula (IV), the above-mentioned auxiliary agent and organic base in the organic In the solvent, the organic solvent solution of phosgene, diphosgene or triphosgene is added dropwise under stirring temperature and stirring for 0.5-3 hours, and then heated and stirred at the reaction temperature for 1-3 hours, until the complete consumption of the reaction substrate is detected .

In the above preferred embodiment, the dropping temperature is preferably -5°C to 10°C, more preferably 0°C to 5°C, and the reaction temperature after the dropping is more preferably 25°C to 80°C.

According to the method for preparing oxazole compounds provided by the present invention, after the reaction of the reaction system is completed, the yield of the reaction product and the formation of by-products are detected by gas chromatography.

The present invention will be described in detail below in conjunction with non-limiting examples.

Example

Preparation of 4-methyl-5-ethoxyoxazole

Example 1

(Use phenylboronic acid as auxiliary):

In the reaction flask, add 24g N-ethoxyoxalanine ethyl ester (0.11mol), 0.13g phenylboronic acid (1.1mmol) and 42.4g triethylamine (0.42mol). After dissolving with 45mL chloroform, Add triphosgene solution (13.1g, 0.044mol, dissolved in 50mL chloroform) dropwise at 0～5℃ and stirring condition, add dropwise in about 1 hour, then heat to 50℃ and react for 1 hour. Gas chromatographic tracking reaction found The raw material N-ethoxyoxalanine ethyl ester is completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-ethoxyoxazole, and its internal standard molar yield was 96% (yield based on N-ethoxyoxalanine ethyl) Ester, internal standard method detection, n-octadecane as internal standard), while only generating 3% (molar yield) of N,N-diethylformyl chloride (yield based on 3 times triphosgene, external standard method detection ).

Comparative example 1 :

In the reaction flask, add 24g of N-ethoxyoxalanine ethyl ester (0.11mol) and 42.4g of triethylamine (0.42mol), dissolve with 45mL of chloroform, and drop at 0～5℃ under stirring conditions. Add triphosgene solution (13.1g, 0.044mol, dissolved in 50mL chloroform), add dropwise in about 1 hour, then increase the temperature to 25～30℃ and react for 2 hours; then heat to 50℃ and react for 3 hours, followed by gas chromatography The reaction found that the raw material N-ethoxyoxalanine ethyl ester was completely consumed. After the reaction, it was confirmed by gas chromatography to confirm that the product obtained was 4-methyl-5-ethoxyoxazole, and its internal standard molar yield was 86% (yield based on N-ethoxyoxalanine ethyl) Ester, detected by internal standard method, n-octadecane is internal standard), and 13% (molar yield) of N,N-diethylformyl chloride is generated at the same time (yield is based on 3 times triphosgene, detected by external standard method) .

Preparation of 4-methyl-5-n-butoxyoxazole

Example 2-1

(Use triethyl phosphate as auxiliary):

In the reaction flask, add 30g N-butoxy oxalylalanine n-butyl ester (0.11mol), 0.9g triethyl phosphite (5.5mmol) and 42.4g triethylamine (0.42mol), and use 45mL triethylamine (0.42mol). After the chloromethane is dissolved, add triphosgene solution (13.1g, 0.044mol, dissolved in 50mL chloroform) dropwise at 0～5°C and stirring. The addition is completed in about 1 hour, and then the reaction is heated to 50°C for 1 hour. Gas chromatography followed the reaction and found that the raw material N-butoxy oxalylalanine n-butyl ester was completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-n-butoxyoxazole, and its internal standard molar yield was 95% (yield based on N-butoxyoxalanine N-Butyl acid, detected by internal standard method, n-octadecane is the internal standard), and only 4% (molar yield) of N,N-diethylformyl chloride is generated (yield is based on 3 times of triphosgene, external Standard).

Comparative example 2 :

In the reaction flask, add 30g N-butoxy oxalylalanine n-butyl ester (0.11mol) and 42.4g triethylamine (0.42mol), dissolve with 45mL chloroform, 0～5℃ and stirring conditions The triphosgene solution (13.1g, 0.044mol, dissolved in 50mL chloroform) was added dropwise to the bottom, and the addition was completed in about 1 hour, and then heated to 50°C for 3 hours. The reaction was followed by gas chromatography and found that the raw material N-butoxy grass The n-butyl acylalanine is completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-n-butoxyoxazole, and its internal standard molar yield was 85% (yield based on N-butoxy oxalanine N-Butyl acid, detected by internal standard method, n-octadecane is internal standard), and 14% (molar yield) of N,N-diethylformyl chloride is generated at the same time (yield is based on 3 times triphosgene, external standard) Law).

Example 2-2

(Use triphenyl phosphine oxide as an additive)

In the reaction flask, add 30g of N-butoxy oxalylalanine n-butyl ester (0.11mol), 0.31g of triphenylphosphine oxide (1.1mmol), 21.2g of triethylamine (0.21mol), and use 45mL of triethylamine. After the chloromethane is dissolved, add dropwise phosgene solution (13.1g, 0.132mol, dissolved in 50mL chloroform) at 0～5°C and stirring. The addition is completed in about 1 hour, and then the reaction is heated to 50°C for 1 hour. Gas chromatography followed the reaction and found that the raw material N-butoxy oxalylalanine n-butyl ester was completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-n-butoxyoxazole, and its internal standard molar yield was 97% (yield based on N-butoxy oxalanine N-Butyl acid, internal standard method detection, n-octadecane as internal standard), while only generating 3% (molar yield) of N,N-diethylformyl chloride (yield based on phosgene, external standard method) .

Example 2-3

(Use tri-tert-butyl phosphine oxide as auxiliary)

In the reaction flask, add 30g N-Butoxy oxalylalanine n-butyl ester (0.11mol), 0.48g tri-tert-butyl phosphine oxide (2.2mmol), 21.2g triethylamine (0.21mol), use 45mL After the chloroform is dissolved, add phosgene solution (13.1g, 0.132mol, dissolved in 50mL chloroform) dropwise at 0～5℃ and stirring, and the addition is completed in about 1 hour, and then heat to 50℃ for 1 hour , Gas chromatography followed the reaction and found that the raw material N-butoxy oxalyl alanine n-butyl ester was completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-n-butoxyoxazole, and its internal standard molar yield was 96% (yield based on N-butoxy oxalylalanine) N-Butyl acid, detected by internal standard method, n-octadecane is internal standard), and only 2% (molar yield) of N,N-diethylformyl chloride is generated (yield based on phosgene, external standard method) .

Preparation of 4-methyl-5-methoxyoxazole

Example 3

(Use triphenyl phosphine oxide as an additive)

In the reaction flask, add 20.8g N-methoxyoxalanine methyl ester (0.11mol) and 42.4g triethylamine (0.42mol), 0.31g triphenylphosphine oxide (1.1mmol), and use 30mL chlorobenzene After dissolving, add dropwise phosgene solution (13.1g, 0.132mol, dissolved in 50mL chlorobenzene) at 0～5℃ and stirring condition, and the dripping is completed in about 1 hour, and then heated to 50℃ for 1.5 hours for reaction, followed by gas chromatography The reaction found that the raw material N-methoxyoxalanine methyl ester was completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-methoxyoxazole, and its internal standard molar yield was 96% (yield based on N-methoxyoxalanine methyl Ester, detected by internal standard method, n-octadecane as internal standard), while generating 2% (molar yield) of N,N-diethylformyl chloride (yield based on phosgene, external standard method).

Comparative example 3

In the reaction flask, add 20.8g N-methoxyoxalanine methyl ester (0.11mol) and 42.4g triethylamine (0.42mol), dissolve with 30mL chlorobenzene, and drop at 0～5℃ under stirring conditions. Add phosgene solution (13.1g, 0.132mol, dissolved in 50mL chlorobenzene), add dropwise in about 1 hour, and then heat to 50°C for 2.5 hours. The reaction was followed by gas chromatography and the raw material N-methoxyoxalanine was found The methyl ester is completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-methoxyoxazole, and its internal standard molar yield was 86% (yield based on N-methoxyoxalanine methyl Ester, detected by internal standard method, n-octadecane is internal standard), and 13% (molar yield) of N,N-diethylformyl chloride is generated at the same time (yield is based on phosgene, external standard method).

Preparation of 4-methyl-5-methoxyoxazole

Example 4

(Use triphenyl phosphine oxide as an additive)

In the reaction flask, add 20.8g N-methoxyoxalanine methyl ester (0.11mol) and 42.4g triethylamine (0.42mol), 0.31g triphenylphosphine oxide (1.1mmol), and use 30mL dichloromethane After the methane is dissolved, add diphosgene solution (13.1g, 0.066mol, dissolved in 50mL dichloromethane) dropwise at 0～5°C and stirring. The addition is completed in about 1 hour, and then the reaction is heated to 50°C for 1.5 hours. Gas chromatography followed the reaction and found that the raw material N-methoxyoxalanine methyl ester was completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-methoxyoxazole, and its internal standard molar yield was 97% (yield based on N-methoxyoxalanine methyl Ester, detected by internal standard method, n-octadecane is internal standard), and 2% (molar yield) of N,N-diethylformyl chloride is generated at the same time (yield is based on 2 times of diphosgene, external standard method) .

Comparative example 4

In the reaction flask, add 20.8g of N-methoxyoxalanine methyl ester (0.11mol) and 42.4g of triethylamine (0.42mol), dissolve in 30mL of dichloromethane, 0～5℃ and under stirring conditions Diphosgene solution (13.1g, 0.066mol, dissolved in 50mL of dichloromethane) was added dropwise, and the addition was completed in about 1 hour, and then heated to 50°C for 2.5 hours. The reaction was followed by gas chromatography and the raw material N-methoxyoxalyl was found Alanine methyl ester is completely consumed. After the reaction, it was confirmed by gas chromatography that the product obtained was 4-methyl-5-methoxyoxazole, and its internal standard molar yield was 88% (yield based on N-methoxyoxalanine methyl Ester, detected by internal standard method, n-octadecane as internal standard), while generating 12% (molar yield) of N,N-diethylformyl chloride (yield based on 2 times diphosgene, external standard method) .

The above examples and comparative examples are summarized in Table 1 below.

Table 1: The raw materials and their amounts, reaction time and products in the Examples and Comparative Examples

It can be seen from Table 1 above that the trihydrocarbyl phosphine oxide represented by the formula (I), the trihydrocarbyl phosphate represented by the formula (II) or the aryl boronic acid compound represented by the formula (III) are used in the reaction system of the present invention. Compared with the comparative examples that do not use these additives, the examples can shorten the reaction time by about 2 hours, increase the yield of the product oxazole compounds to more than 95%, and reduce the by-products N, N by more than 10%. -Diethylformyl chloride.

Claims

A method for preparing oxazole compounds, characterized in that: the method comprises: adding a trihydrocarbyl phosphine oxide selected from the following formula (I), a trihydrocarbyl phosphate represented by the following formula (II), and the following formula ( III) One or more auxiliary agents in the aryl boronic acid compound represented by the following formula (IV) and the organic solvent solution of the oxalylated amino acid ester compound and organic base are added selected from phosgene and diphosgene React with one or more organic solvent solutions in triphosgene to obtain the oxazole compound represented by formula (V):

Wherein, in formula (I), each R 1 is the same or different, and is selected from an alkyl group containing 1 to 20 carbon atoms, a cycloalkyl group containing 3 to 20 carbon atoms, or a substituent containing 6 to 20 carbon atoms Or unsubstituted aryl; preferably methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, hexyl, cyclohexyl, octyl, n-undecyl, phenyl, p-toluene Group, or p-methoxyphenyl; more preferably phenyl, p-methylphenyl, t-butyl, or cyclohexyl;

In formula (II), each R 2 is the same or different, and is selected from an alkyl group containing 1-20 carbon atoms, a cycloalkyl group containing 3-20 carbon atoms, or substituted or unsubstituted 6-20 carbon atoms. Substituted aryl groups; preferably methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, hexyl, cyclohexyl, octyl, n-undecyl, phenyl, p-methylphenyl, Or p-methoxyphenyl; more preferably phenyl, ethyl, or isopropyl;

In formula (III), each R 3 is the same or different, and is selected from hydrogen or an alkyl group containing 1 to 10 carbon atoms;
Is a substituted or unsubstituted aryl group containing 6-20 carbon atoms; preferably phenyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl, or naphthyl;

In formulas (IV) and (V), each R 4 is the same or different, and is selected from alkyl groups containing 1 to 5 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, or n-butyl ; R 5 is H or an alkyl group containing 1 to 5 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, or n-butyl.
The method for preparing an oxazole compound according to claim 1, wherein the ratio of the mass of the oxalylated amino acid ester compound represented by the formula (IV) to the total volume of the organic solvent in the reaction system is 0.05 g/mL ~1.0g/mL, preferably 0.1g/mL~0.5g/mL.
The method for preparing oxazole compounds according to claim 1 or 2, wherein the amount of the auxiliary agent is 0.01 to 0.2 equivalents of the oxalylated amino acid ester compound represented by the formula (IV), preferably 0.05 to 0.1 equivalent.
The method for preparing oxazole compounds according to any one of claims 1 to 3, wherein the amount of the organic base is 0.06 to 6 equivalents of the amount of phosgene, preferably 1 to 6 equivalents; or double light 0.12-12 equivalents of the amount of gas, preferably 2-12 equivalents; or 0.18-18 equivalents of the amount of triphosgene, preferably 3-18 equivalents.
The method for preparing oxazole compounds according to any one of claims 1 to 4, wherein the amount of the phosgene is 1 to 3 equivalents of the oxalylated amino acid ester compound represented by the formula (IV), preferably 1 to 2 equivalents; the amount of diphosgene is 0.5 to 1.5 equivalents, preferably 0.5 to 1 equivalent of the oxalylated amino acid ester compound represented by the formula (IV); the amount of triphosgene is the formula ( IV) 0.33-1 equivalent of the oxalylated amino acid ester compound represented, preferably 0.33-0.7 equivalent.
The method for preparing oxazole compounds according to any one of claims 1-5, wherein the reaction temperature is -10°C to 180°C, preferably 25°C to 100°C.
The method for preparing oxazole compounds according to any one of claims 1 to 6, wherein the trihydrocarbyl phosphine oxide represented by the formula (I) is triphenyl phosphine oxide, tri-p-methylphenyl phosphine oxide, One or more of tri-tert-butyl phosphine oxide and tricyclohexyl phosphine oxide;

The trihydrocarbyl phosphate represented by formula (II) is one or more of triphenyl phosphate, triethyl phosphate, and triisopropyl phosphate;

The arylboronic acid compound represented by the formula (III) is one or more of phenylboronic acid, naphthaleneboronic acid, p-methoxyphenylboronic acid, and p-tolueneboronic acid.
The method for preparing oxazole compounds according to any one of claims 1-7, wherein the oxalylated amino acid ester compound represented by formula (IV) is N-ethoxyoxalanine ethyl ester, N -One or more of n-butoxy oxalyl alanine n-butyl ester and N-methoxy oxalyl alanine methyl ester.
The method for preparing oxazole compounds according to any one of claims 1-8, wherein the organic base is pyridine, diisopropylethylamine, dimethylamine, triethylamine, 4-N,N -One or more of dimethylaminopyridine and 4-methylimidazole, preferably triethylamine.
The method for preparing oxazole compounds according to any one of claims 1-9, wherein the organic solvent is dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2- Trichloroethane, chlorobenzene, toluene, xylene, N,N-dimethylformamide, methyl tert-butyl ether, isopropyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, One or more of 2-methyltetrahydrofuran, cyclohexane, n-hexane, and petroleum ether; preferably dichloromethane, trichloromethane, 1,1,2-trichloroethane, chlorobenzene, toluene, dichloromethane, One or more of toluene, N,N-dimethylformamide, cyclohexane, n-hexane, and petroleum ether.